No abstract

The present study aimed to investigate the effect of metformin on the induction of autophagy in the liver and adipose tissues of a mouse model of obesity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity-associated hepatic steatosis, and treated with metformin (150 mg/kg/d) by intraperitoneal injection for the final 4 weeks of HFD feeding. Body weight was recorded weekly, and the food intake of the mice was recorded daily during the treatment period. Liver and adipose tissues were harvested for histological and molecular analyses. The results revealed that metformin significantly reduced body weight without altering food intake in the HFD mice, particularly in the epididymal white adipose tissue (eWAT). Metformin treatment ameliorated HFD-induced hepatic steatosis and serum levels of triglycerides, which was consistent with a marked increase in the expression levels of microtubule-associated protein 1 light chain 3 (LC3) and AMP-activated protein kinase (AMPK) in the liver following metformin treatment. However, metformin suppressed the expression of LC3 in the eWAT without altering the expression of AMPK, compared with that in the HFD mice. In conclusion, metformin reduced the body weight and hepatic steatosis of the HFD-induced obese mice, without altering food intake. The effects of metformin treatment may be attributable to the improved induction of hepatic autophagy and the inhibited induction of adipose tissue autophagy.

Objective: Cell death-inducing DFF45-like effector C (CIDEC) is a lipid droplet-coating protein that promotes triglyceride accumulation and inhibits lipolysis. TNF-a downregulates CIDEC levels to enhance basal lipolysis, whereas CIDEC overexpression could block this effect. This study aimed to investigate the signaling pathway of TNF-a-mediated CIDEC downregulation in human adipocytes. Methods: First CIDEC expression was detected in adipose tissue of lean and human subjects with obesity. Next, the temporal-and dose-dependent effects of TNF-a on CIDEC expression in human SW872 adipocytes were investigated. Selective inhibitors or RNAi or constitutively active MEK1 mutant was used to suppress or stimulate MEK/ERK cascade. Immunofluorescence and subcellular fractionation technique were used to study PPARc redistribution after TNF-a treatment. Reporter assay was performed to confirm the direct effects of TNF-a on CIDEC transcription. Results: CIDEC expression decreased in adipose tissue of subjects with obesity and negatively correlated with adipose TNF-a levels and systemic lipolysis. TNF-a reduced CIDEC expression in vitro, but suppression of MEK/ERK cascade prevented TNF-a-mediated CIDEC downregulation. PPARc, the transcription factor of CIDEC, was phosphorylated and redistributed by TNF-a in a MEK/ERK-dependent manner. Reporter assay confirmed that TNF-a reduced CIDEC transcription. Conclusions: TNF-a downregulates CIDEC expression through phosphorylation and nuclear export of PPARc by MEK/ERK cascade.

Serum SFRP5 is regulated by weight status and seems to be correlated with metabolic disorders in children.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver disorders that is featured by the extensive deposition of fat in the hepatocytes. Current treatments are very limited due to its unclear pathogenesis. Here, we investigated the function of circ_0057558 and miR-206 in NAFLD. High-fat diet (HFD) feeding mouse was used as an in vivo NAFLD model and long-chain-free fatty acid (FFA)-treated liver cells were used as an in vitro NAFLD model. qRT-PCR was used to measure levels of miR-206, ROCK1 mRNA, and circ_0057558, while Western blotting was employed to determine protein levels of ROCK1, p-AMPK, AMPK, and lipogenesis-related proteins. Immunohistochemistry were performed to examine ROCK1 level. Oil-Red O staining was used to assess the lipid deposition in cells. ELISA was performed to examine secreted triglyceride (TG) level. Dual-luciferase assay was used to validate interactions of miR-206/ROCK1 and circ_0057558/miR-206. RNA immunoprecipitation was employed to confirm the binding of circ_0057558 with miR-206. Circ_0057558 was elevated while miR-206 was reduced in both in vivo and in vitro NAFLD models. miR-206 directly bound with ROCK1 3’-UTR and suppressed lipogenesis and TG secretion through targeting ROCK1/AMPK signaling. Circ_0057558 directly interacted with miR-206 to disinhibit ROCK1/AMPK signaling. Knockdown of circ_0057558 or overexpression of miR-206 inhibited lipogenesis, TG secretion and expression of lipogenesis-related proteins. ROCK1 knockdown reversed the effects of circ_0057558 overexpression. Injection of miR-206 mimics significantly ameliorated NAFLD progression in vivo. Circ_0057558 acts as a miR-206 sponge to de-repress the ROCK1/AMPK signaling and facilitates lipogenesis and TG secretion, which greatly contributes to NAFLD development and progression.